盡管在多年前已經(jīng)知道,，“乳腺癌基因”BRCA1的缺陷能夠增加人患乳腺癌的風(fēng)險,，但是它如何導(dǎo)致腫瘤生長卻仍然是個謎,。
在10月15日的《癌癥研究》（Cancer Research）雜志上，來自美國芝加哥大學(xué)和日本京都大學(xué)的研究人員的新研究揭示出一種正常情況下修復(fù)受損DNA的機(jī)制可能在BRCA1功能異常時導(dǎo)致乳腺癌的發(fā)生,。
他們的新發(fā)現(xiàn)使得對正常BRCA1基因如何抑制腫瘤的生長以及遺傳穩(wěn)定性本質(zhì)有了更進(jìn)一步的了解,。
領(lǐng)導(dǎo)這項研究的Douglas Bishop和同事發(fā)現(xiàn)，因缺少BRCA1導(dǎo)致的生長緩慢可能通過增加DNA修復(fù)蛋白RAD51而得到補(bǔ)償,。
RAD51與同源重組有關(guān),，而同源重組則是細(xì)胞修復(fù)受損DNA的一種常用方法。在同源重組中,，生物體利用未斷裂的染色體拷貝作為模板來修復(fù)斷裂的染色體,。
BRCA1本身能通過重組來促進(jìn)DNA修復(fù)，并且通常的觀點(diǎn)認(rèn)為BRCA1的喪失是由于DNA修復(fù)的失敗而導(dǎo)致腫瘤發(fā)生的,。這項新的研究則挑戰(zhàn)了這個經(jīng)典理論,。
Bishop指出，BRCA1缺陷本身可能并不會導(dǎo)致腫瘤的發(fā)生,，但是試圖通過增加RAD51水平來補(bǔ)償修復(fù)過程中的BRCA1缺陷的細(xì)胞則可能比普通細(xì)胞的遺傳穩(wěn)定性要差一些,，因此更容易形成腫瘤。
利用一個公共數(shù)據(jù)庫,，Bishop和同事分析了117個原發(fā)性乳腺腫瘤的基因組數(shù)據(jù),，并發(fā)現(xiàn)其與同源重組有關(guān)的基因的RNA水平增加了。他們發(fā)現(xiàn),，RAD51和另外兩個關(guān)鍵的附屬因子的基因的RNA水平在BRCA1缺陷腫瘤中明顯高于與BRCA1突變無關(guān)的乳腺腫瘤樣本,。
原文出處：
Public release date: 15-Oct-2007
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Contact: John Easton
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University of Chicago Medical Center
Enhanced DNA-repair mechanism can cause breast cancer
Although defects in the "breast cancer gene," BRCA1, have been known for years to increase the risk for breast cancer, exactly how it can lead to tumor growth has remained a mystery. In the October 15, 2007, issue of the journal Cancer Research, scientists from the University of Chicago and Kyoto University, Japan, suggest that a mechanism that normally repairs damaged DNA may function abnormally in BRCA1 carriers leading to one type of poor-prognosis breast cancer.
Their findings provide insight into how the normal BRCA1 gene suppresses the growth of tumors as well as the nature of the genetic instability that leads to cancer when BRCA1 is defective.
"If you take a normal, healthy cell and get rid of BRCA1, you end up with an unhealthy, slow-growing cell," said Douglas Bishop, PhD, associate professor of radiation and cellular oncology at Chicago and principal investigator of the study. "That抯 a bit of a paradox, because loss of BRCA1 also causes tumors and tumor formation is not normally associated with poor cell growth."
Bishop and colleagues found that the slow growth caused by loss of BRCA1 could be compensated for by increasing the amount of the DNA repair protein RAD51.
RAD51 is involved in homologous recombination, a method used by cells to repair damaged DNA. In homologous recombination, organisms heal broken chromosomes using an unbroken chromosome copy as a template.
BRCA1 itself promotes DNA repair through recombination and the conventional view is that loss of BRCA1 causes tumors because DNA repair fails. The new work from Bishop and colleagues challenges this view.
"BRCA1-deficiency by itself would probably not cause a tumor," Bishop said, "but cells that manage to compensate for the BRCA1 defect in repair by ramping up RAD51 levels are likely to be less genetically stable than normal cells and therefore more prone to form tumors."
Using a public database, Bishop and colleagues examined genomic data from 117 primary breast tumors for evidence of elevated levels of RNAs for genes involved in homologous recombination. They found that the level of RNA for three genes -- RAD51 and two of its key accessory factors -- was significantly higher in BRCA1-deficient tumors compared with breast tumors that were not associated with BRCA1 mutations.
"High levels of RAD51 may help cells that lack BRCA1 overcome the defects in recombination caused by loss of BRCA1," Bishop said, "but the recombination that occurs in this situation may be abnormal and may actually cause mutations which in turn lead to the development of a tumor."
When the researchers took normal, healthy cells in culture and disabled the BRCA1 gene, the cells survived, but grew slowly and were unable to repair DNA damage normally. When Bishop and his coworkers increased the amount of RAD51 in these cells, however, the ability of cells to repair DNA damage was restored and the mutated cells grew more quickly.
In the future "it will be interesting to determine whether high levels of RAD51 can predict tumor prognosis," said Bishop. "Its also possible that tumor cells with high levels of RAD51 are particularly dependent on that gene for survival and therefore sensitive to drugs that target RAD51"
The National Cancer Institute funded the work done at the University of Chicago and the CREST Research Project, Japan Science and Technology, Kyoto funded the effort in Japan. Additional authors of the paper include Richard D. Martin, Brian J. Orelli and Andy J. Minn from Chicago, and Mitsuyoshi Yamazoe and Shunichi Takeda of Kyoto University.
